The last several years have seen the identification of a large number of sequence-specific DNA binding proteins that are important for gene regulation. These proteins use a small number of DNA binding motifs to interact with DNA. This laboratory is focusing on two related motifs that interact with DNA in a sequence-specific manner, the bZIP and the bHLH-Zip motifs. Both motifs bind as dimers to abutted dyad symmetric DNA sequences. We have proposed molecular models for both motifs. We are testing aspects of our models using site directed mutagenesis and chemical probing of DNA structure. Currently, the laboratory is focusing on the dimerization of the bZIP motif, a region termed the leucine zipper. Structural studies indicate that the leucine zipper is a new name for a structure proposed 40 years ago, the coiled-coil. Our structural modeling and experimental results suggest that any bZIP protein could potentially interact with any other bZIP protein to form a dimer bound to DNA. The question is to understand the structural determinants that determine dimerization specificity. Using simple rules of interhelical salt bridge formation, we have predicted novel interactions among known mammalian bZIP proteins. Using the same rules we have designed bZIP proteins that interact with the protein C/EBP better than C/EBP interacts with itself. This engineering of "Dominant-Negative" molecules will be used in a genetic type fashion to help unravel the biological function of C/EBP.